Relevance to Autism

Two de novo missense variants that were predicted in silico to be damaging were identified in the KCND3 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified KCND3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05). Haplotype blocks associated with the KCND3 gene had previously been shown to associate with non-verbal communication in families from the Autism Genetics Research Exchange (AGRE) and the Autism Genome Project (AGP) (Lu et al., 2013). Inherited and de novo mutations in the KCND3 gene are also associated with a form of autosomal dominant spinocerebellar ataxia (SAC19; OMIM 607346), an ataxia syndrome in which affected individuals frequently display cognitive impairment/intellectual disability and epilepsy (Lee et al., 2012; Duarri et al., 2012; Smets et al., 2015; Kurihara et al., 2017; Huin et al., 2017). Functional analysis of the ASD-associated p.Arg86Pro missense variant, which was originally identiified in an SSC proband, in Drosophila in Marcogliese et al., 2022 demonstrated a possible loss-of-function effect (increased movement and decreased grooming behavior compared to humanized reference; failure to reduce expected viability to the extent of corresponding reference allele upon ubiquitous overexpression).

Molecular Function

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential.

External Links

References